1. Design, synthesis, and structure-activity relationships of novel pyrazolo[5,1-b]thiazole derivatives as potent and orally active corticotropin-releasing factor 1 receptor antagonists
- Author
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Kaoru Murata-Tai, Shigeki Hibi, Yoshinori Takahashi, Taro Terauchi, Kogyoku Shin, Kunitoshi Takeda, Hisashi Shibata, Masahiro Yonaga, Masae Fujisawa, Minako Hashizume, Mitsuhiro Ino, Kodo Shikata, and Ryota Taguchi
- Subjects
Male ,Models, Molecular ,Stereochemistry ,Corticotropin-Releasing Hormone ,Administration, Oral ,Receptors, Corticotropin-Releasing Hormone ,Rats, Sprague-Dawley ,chemistry.chemical_compound ,Mice ,Radioligand Assay ,Structure-Activity Relationship ,Adrenocorticotropic Hormone ,Cell Line, Tumor ,Drug Discovery ,Cyclic AMP ,Animals ,Humans ,Thiazole ,Receptor ,Defecation ,Mice, Inbred BALB C ,Rats, Inbred F344 ,Rats ,Thiazoles ,Orally active ,HEK293 Cells ,chemistry ,Design synthesis ,Anti-Anxiety Agents ,Drug Design ,Molecular Medicine ,Pyrazoles - Abstract
This paper describes the design, synthesis, and structure-activity relationships of a novel series of 7-dialkylamino-3-phenyl-6-methoxy pyrazolo[5,1-b]thiazole derivatives for use as selective antagonists of the corticotropin-releasing factor 1 (CRF(1)) receptor. The most promising compound, N-butyl-3-[4-(ethoxymethyl)-2,6-dimethoxyphenyl]-6-methoxy-N-(tetrahydro-2H-pyran-4-yl)pyrazolo[5,1-b][1,3]thiazole-7-amine (6t), showed high affinity (IC(50) = 70 nM) and functional antagonism (IC(50) = 7.1 nM) for the human CRF(1) receptor as well as dose-dependent inhibition of the CRF-induced increase in the plasma adrenocorticotropic hormone (ACTH) concentration at a dose of 30 mg/kg (po). Further, in the light/dark test in mice, the compound 6t showed anxiolytic activity at a dose of 30 mg/kg (po).
- Published
- 2012